DESCRIPTION (Applicant's abstract): Highly active antiretroviral therapy (HAART) suppresses HIV burdens and reduces mortality in AIDS. This project will determine the impact that HAART, by lowering HIV burden, has had on syndromes of paraplegia, pain, and sensorimotor deficits. These syndromes and the underlying pathologies, myelopathy and neuropathy, are highly prevalent in AIDS. AIM I will address the problem prospectively in 80 longitudinally studied subjects selected for having signs, symptoms, or risk factors of these syndromes. We will draw our cohort from a large community clinic population in Texas associated with the National NeuroAIDS Tissue Consortium (NNTC). The cohort from this ethnic- and gender-diverse clinic pool will be followed at least four years. At regular intervals they will receive neurology examinations, pain inventories neurophysiological tests, plasma HIV burden assays, and assays of immune function. A multivariate analysis will be performed to determine how cumulative HIV burdens relate to the onset and progression of the signs, symptoms, and physiologic abnormalities present in AIDS-associated neuropathy and myelopathy. This analysis will also examine how taking neurotoxic HAART drugs influences these syndromes adjusting for immune status. AIM 2 will address the issue by examining pathological outcomes in a cohort of subjects with end-stage AIDS who are being followed longitudinally to autopsy in the NNTC project (projected n = 350). Longitudinal measures of neurological functions, pain status, and HIV burdens will be compared with pathological and neurochemical indexes of tissue damage at autopsy. Relationships between HIV burdens and prevalences of myelopathy and neuropathy in spinal cord and nerve specimens will be analyzed. Neuropathological outcomes will be augmented with neurochemical quantification of active nerve fiber loss and tissue cytokines that could mediate neurological dysfunction. Analysis of covariance will be used to determine how immune status and taking neurotoxic HAART drugs influence the neuropathological outcomes. AIM 3 will approach the problem retrospectively using a unique asset. We archived fresh spinal cord and sural nerve specimens over a period of 13 years spanning from the pre-AZT, pre-neurotoxic, pre-protease inhibitor, and the post-HAART eras. We will compare the prevalences and severities of myelopathy and neuropathy in specimens from the changing treatment eras. Pathology again will be backed up by neurochemical assays, and the influence of neurotoxic HAART drugs will be examined. Together, the studies we have proposed will provide insights concerning prevalent AIDS morbidities in the HAART era.